6-31936002-A-G

Position:

• chr6-31936002-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000063.6(C2):​c.929A>G​(p.Asn310Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 1,613,058 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00048 (3 hom.)
• Consequence: C2 NM_000063.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.348

Genes affected

C2 (HGNC:1248): (complement C2) Component C2 is a serum glycoprotein that functions as part of the classical pathway of the complement system. Activated C1 cleaves C2 into C2a and C2b. The serine proteinase C2a then combines with complement factor 4b to create the C3 or C5 convertase. Deficiency of C2 has been reported to associated with certain autoimmune diseases and SNPs in this gene have been associated with altered susceptibility to age-related macular degeneration. This gene localizes within the class III region of the MHC on the short arm of chromosome 6. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described in publications but their full-length sequence has not been determined.[provided by RefSeq, Mar 2009]

C2-AS1 (HGNC:49464): (C2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027373105).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C2	NM_000063.6	c.929A>G	p.Asn310Ser	missense_variant	7/18	ENST00000299367.10	NP_000054.2
C2-AS1	NR_104191.1	n.541-600T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C2	ENST00000299367.10	c.929A>G	p.Asn310Ser	missense_variant	7/18	1	NM_000063.6	ENSP00000299367	P1
C2-AS1	ENST00000630806.1	n.541-600T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152178 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000564 AC: 139 AN: 246664 Hom.: 0 AF XY: 0.000550 AC XY: 74 AN XY: 134438

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000786

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000481 AC: 703 AN: 1460762 Hom.: 3 Cov.: 31 AF XY: 0.000479 AC XY: 348 AN XY: 726700

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.000554

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152296 Hom.: 0 Cov.: 31 AF XY: 0.000376 AC XY: 28 AN XY: 74476

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000564 Hom.: 1

Bravo AF: 0.000374

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000331 AC: 1

ESP6500EA AF: 0.000738 AC: 4

ExAC AF: 0.000598 AC: 71

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complement component 2 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Age related macular degeneration 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 310 of the C2 protein (p.Asn310Ser). This variant is present in population databases (rs144201432, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with C2-related conditions. ClinVar contains an entry for this variant (Variation ID: 907958). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.41
DANN	Benign	0.53
DEOGEN2	Benign	0.068	T;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.070	.;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	-0.72	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.016
MVP		0.57
MPC		0.24
ClinPred		0.0040	T
GERP RS		-1.5
Varity_R		0.12
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144201432; hg19: chr6-31903779;